Tumor is a disease which seriously threatens the life of human. It is great important to investigate and develop safe and effective anti-tumor drugs for improving the life quality of human.
Taxanes (including paclitaxel (PTX), docetaxel (DTX), cabazitaxel and larotaxel) are a class of very effective and broad-spectrum anti-tumor drugs. Its mechanism of action mainly includes polymerizing and stabilizing the microtubules, making the rapidly-divided tumor cells fixed on the stage of mitosis, blocking the replication of cancer cells and leading the cells death. It has been demonstrated in experiments in vitro that the taxanes had a significant radiosensitizing effect, and made the cells to suspend to G2 and M phases, during which the cells were sensitive to radiotherapy. However, almost all of the taxanes are highly hydrophobic and have low oral absorption, and the only route of administration thus far is injection. Because of the difficulty in preparing an aqueous solution of the taxanes, surfactants were often added in the commercially available formulations to increase the solubility of the drugs. However, there are many disadvantages for the solubilization method: (1) either polyoxyethylenated castor oil (Cremophor® EL) which is used as a solubilizer for paclitaxel (trade name: Taxol) or Tween 80 which is used as a solubilizer for docetaxel (trade name: Taxotere) and cabazitaxel (trade name: JEVTANA), easily causes allergy; therefore, patients need to accept anti-allergy treatment before using the drug; (2) the stability of the drug is poor, and the availability after injection is not high: drugs in the above formulations are easily precipitated upon diluting; the drugs must be subjected to a special filter before administration; the solution for injection has to be diluted slowly, and the precipitation degree of the drug often varies with different operators, which results in an inaccurate amount of drug injected into the body and then different therapeutic efficacy; (3) the hematologic toxicity is high: both of Cremophor® EL and Tween 80 can cause hematologic toxicity, which is the major factor restricting the improvement of the therapeutic dosage.
Doxorubicin is an anti-tumor antibiotic and belongs to cytotoxic drugs, like taxanes. It inhibits the synthesis of RNA and DNA, and has the strongest inhibition on RNA. It has a broad spectrum of anti-tumor and is effective to a variety of tumors. As a non-specific drug for cell cycle, doxorubicin can kill the tumor cells of various growth stages. Doxorubicin is mainly used in the treatment of acute leukemia, acute lymphoblastic leukemia and myeloid leukemia. Conventional formulations of Doxorubicin have side effects such as significant cardiac toxicity and bone marrow suppression.
Epirubicin, an isomer of Doxorubicin, has equal or slightly higher therapeutic efficacy and lower toxicity to heart, as compared with Doxorubicin.
Curcumin has received widespread attention in recent years as a non-cytotoxic drug with potential anti-tumor activity. The prominent feature of curcumin lies in that it has few side effect and has adjuvant therapeutic effects like anti-inflammatory, anti-oxidation, etc. The greatest drawback of curcumin is the low water solubility. Preparation of stable aqueous formulation of curcumin has attracted increasing attention in recent years.
Polymeric micelles have been developed as a novel drug delivery system in recent years. The micelles are usually formed by the orientation of a large amount of molecular chains on amphiphilic block copolymers. Drugs are encapsulated in the micellar core by weak interaction between the hydrophobic segment of the block copolymer and the drug molecules, and the hydrophilic segment is outward to stabilize the micelle, forming a typical core-shell structure. Polymeric micelles can not only increase the solubility of drugs and the therapeutic dosage, but also avoid the degradation and inactivation of drugs and reduce the toxicity by encapsulating the drugs therein. The diameter of the micelle is usually less than 100 nm, and the shell is usually segment of hydrophilic PEG; thus, they are able to avoid the phagocytosis of reticuloendothelial system (RES), increase the circulation time and achieve the passive targeting to tumors through EPR effect (enhanced permeability and retention effect). In addition, due to their high molecular weight, the polymeric micelles are able to avoid the renal clearance. Compared with small molecular surfactant, the CMC (critical micelle concentration) of polymeric micelle is much lower, and the micellar structure is maintained stable even upon dilution. The drug loading efficiency of the micellar drug-loaded system can reach 25%, which is able to fulfill the requirement of clinical dosage. At the same time, the polymeric materials are biodegradable and biocompatible.
Polymeric micelles are considered to be a novel drug delivery system with great potential, particularly for the anti-tumor drugs with poor solubility. However, their relatively low stability in solution has become the key problem for transferring this novel drug delivery system into clinical research. Particularly, the stability of taxane micelle is generally poor. The paclitaxel micelle for injection (trade name: Genexol PM) which is firstly approved in Korea, for example, keeps stable for no more than 24 h in solution at room temperature (Lee S W, et al, Ionically Fixed Polymeric Nanoparticles as a Novel Drug Carrier, Pharmaceutical Research, 2007, 24: 1508-1516). Samyang Corporation has made a great effort to improve the stability of paclitaxel micelles. For example, it was disclosed in CN01809632.8 that the terminal hydroxyl group of block copolymer was end-capped with acetoxy or benzoyl to increase the compatibility between the hydrophobic segment and the drug, and thus improving the stability of the micelle. However, the micelle prepared with the copolymer kept stable for just 3 days at room temperature in vitro, and the in vivo stability of the micelle was lower. The stability of micellar solution of docetaxel or cabazitaxel, which are the derivatives of paclitaxel, is even lower. Up to date, taking docetaxel micelle for example, there are few cases wherein it could be transferred to clinical study, and the key factor is the poor stability of the micelle solution (Gaucher G, et al. Polyester-based micelles and nanoparticles for the parenteral delivery of taxanes, Journal of Controlled Release, 2010, 143: 2-12). Taking Nanoxel PM™ micelle (wherein mPEG-PLA is used as the polymeric excipient, docetaxel is used as the drug) of Korea Samyang Corporation for instance, when the drug loading efficiency of the micelle is 5% and the drug concentration is 0.1-2 mg/ml, the micelle is stable at room temperature for only 6 h (Lee S W, et al, Development of docetaxel-loaded intravenous formulation, Nanoxel-PM™ using colymer-based delivery system, Journal of Controlled Release, 2011, 155: 262-271). The micelle disintegrates rapidly after been administrated to the body, and the drug immediately binds to the protein in blood (such as albumin); therefore, the EPR effect of the micelle is dismissed. The results of animal experiments showed that there is no difference in the drug efficacy between Nanoxel PM™ micelles and docetaxel injection, and there is no improvement in the most tolerated doses either; thus, there are no significant advantages of Nanoxel PM™ micelles. On the other hand, due to the structural similarity between docetaxel and cabazitaxel, the stability of cabazitaxel mPEG-PLA micelle is similar to that of docetaxel. It has been found in our study that when the drug concentration in mPEG-PLA/cabazitaxel micelle is 5 mg/mL, the micellar solution kept stable at room temperature for no longer than 2 h. Neither the in vivo efficacy nor the safety is improved effectively. In addition, there is large difficulty for the preparation of such unstable micelles in large-scale.
Taxanes are among the greatest discoveries in the research and development of anti-tumor drug in the last 20 years, and will remain as a main anti-tumor drug in the next 20 years. Due to its dose-limiting toxicity, the main focus for investigators has always been on fully utilizing the drug efficacy. As a great potential delivery system for taxanes, the instability of the micelles has become the biggest flaw of this drug delivery system, and the reasons causing such instability are still unclear. researchers have made great efforts to improve the stability of taxanes-encapsulated micelles. For example, as disclosed in the patent 201010001047, to improve the stability of paclitaxel micelle, amino acids were added to the micelle solution (the amino acids were added during the formation of the micelles), but in the disclosure there is no information about the location of amino acids in the micelles (only as a physical barrier agent of the micelle or co-present molecules with drug molecules in the hydrophobic core of the micelle). Meanwhile, as an auxiliary additive, it is unknown whether the amino acid is still able to maintain the micellar stability after administration to the body and dilution by blood; thus, the drug effect in vivo is still unclear. Moreover, it is reported that entrapping paclitaxel and docetaxel together in a copolymer micelle can significantly increase the drug loading efficiency and the stability of the micelle; but this binary-drug loaded micelle has not been recognized in clinical yet (Shao Cheng Wei, etc., In vitro stability of paclitaxel and docetaxel binary-drug loaded micelles, Journal of China Pharmaceutical University, 2010, 41:428-434). Huh et al synthesized a micelle with the block copolymer of PDENA-PEG. The micelle showed long-term stability after encapsulating paclitaxel, but the insufficient data supporting safety of the polymer materials present great security challenges for clinical use (Huh K M, et al. Hydmtropic polymer micelle system for delivery of paclitaxel. Journal of Controlled Release, 2005, 101 (1-3):59-68).